Epidemiological data have demonstrated that the prevalence of either obesity or hepatocellular carcinoma (HCC) is increasing worldwide during past decades, and obesity has been unequivocally shown to be a risk factor for HCC. It has been reported that a significant proportion of HCC in obesity develops in cryptogenic cirrhosis, which is largely associated with the progression of nonalcoholic fatty liver disease, especially nonalcoholic steatohepatitis. Since the HCC is a highly malignant tumor with a poor prognosis, a better understanding of the molecular mechanisms may help researchers to explore new approaches for preventing and treating the obesity-related HCC, and thereby facilitating a substantial reduction of morbidity and mortality. In this article, we reviewed the mechanisms underlying the relationship between obesity and HCC, with an emphasis on the roles of insulin/insulinlike growth factor axis, adipose tissue derived hormones, oxidative stress, and liver stem cells. In addition, we will discuss the impact of life-style modification on obesityrelated HCC.